The development and evolution of CF lung disease can be variable, but it is clear from our previous research that physiological and structural defects begin in infancy and are frequently present prior to the detection of bacterial infection, implicating other etiologies or infectious insults. Little is known about the impact of viruses on bacterial colonization, airway inflammation, physiological measures, and structural changes in the CF lung. In this proposal, we will define the role(s) of viral infections in the origins of eary CF pulmonary disease. Combining the expertise and resources available at the University of Indiana (Indianapolis, Indiana), Washington University (St. Louis, Missouri), and the Australian Early Surveillance Team for Cystic Fibrosis (AREST CF) (Melbourne and Perth, Australia), we will define the incidence and type of viral infections in CF infants. Bronchoalveolar lavage fluid and pharyngeal secretions will be collected at predetermined times during infancy, and highly sensitive nucleic acid-based detection and powerful microbiomic assays will be used to characterize lower respiratory tract infections. Also, we will systematically define the earliest physiological changes in the CF lung, combining analyses for inflammatory markers in lavage fluid, pulmonary function measurements, and computerized x-ray tomographic imaging, in a surveillance program for infants diagnosed shortly after newborn screening. Innovative airway modeling techniques will be applied to better detect and measure airway disease that precedes bronchiectasis. We will examine the relationship between viral infections and initial pathophysiological changes in the CF lung, and test the hypothesis that early respiratory viral infections alter the bacterial flora and inflammatory profile in the airway and accelerate progression of pulmonary disease in CF infants. The proposal has three Specific Aims, which will (i) define the frequency of respiratory virus infections and their impact on the evolution of endobronchial bacterial infection and inflammation in CF infants; (ii) examine the impact of early virus infections on the development of respiratory symptoms and physiological changes in the lungs of CF infants; and (iii) evaluate the relationship between virus infections and airway disease as de- fined by structural and airway modeling techniques. If successful, these studies will provide new insights into the pathogenesis of CF lung disease, aid the design of therapeutic strategies to reduce virus-induced pulmonary morbidity, and potentially prevent the development of irreversible airway disease. (End of Abstract)